Combination antiretroviral therapy (cART) has transformed HIV into a complex chronic disease but does not fully restore health. Although the reasons for this fact are not clear, likely causes include chronic immune activation, alcohol use, and multimorbidity. Even when HIV infection is suppressed, it is associated with chronic activation of the immune system. Alcohol use and multimorbidity are common among those aging with HIV infection (HIV+) and they lead to immune activation. Chronic immune activation is associated with immune dysfunction, organ system injury, and death. HIV, alcohol use, multimorbidity and polypharmacy resulting from HIV and multimorbidity can cause direct organ system injury. To better understand this process we propose to enroll 200 HIV infected cART (and antiretroviral) naive individuals and 100 uninfected individuals (HIV-) from the Veterans Aging Cohort Study. Our specific aims are to (1) collect and bank serial biospecimen samples among HIV+ individuals initiating cART and demographically and behaviorally similar uninfected comparators and to begin to use these samples to characterize (2) the longitudinal associations of alcohol use and multimorbidity on immune function and (3) alcohol use and polypharmacy on organ system injury as measured by the VACS index and its components. Among HIV+ we will collect specimens before and after cART initiation. We hypothesize that alcohol, multimorbidity, polypharmacy and immune dysfunction will be present in all age groups of both groups and that alcohol, multimorbidity, and polypharmacy will be associated with increasing immune dysfunction and end organ damage. Alcohol use will be assessed by self-report and phosphatidyl ethanol. These aims are critical if we are to understand how aging and alcohol use with HIV differs from aging and alcohol use among uninfected similar comparators. This work will help characterize immune dysfunction and organ system injury among aging individuals who drink alcohol. Lastly, these longitudinal specimens can be linked with adjudicated clinical outcomes and subclinical disease measures among HIV+ and demographically and behaviorally similar uninfected people to provide a unique and valuable resource for investigators within and outside the VACS community. PUBLIC HEALTH RELEVANCE: We propose to examine whether changes in alcohol consumption, multimorbidity, and polypharmacy are associated with changes in immune dysfunction and mortality risk among HIV+ and matched uninfected people. As part of this study we will be storing specimens that can be used for future studies with other research collaborators to maximize the utility of these specimens for scientific discovery